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OBJECTIVE The sodium–glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole. RESEARCH DESIGN AND METHODS SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2i at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. RESULTS In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49–1.28]), as did dapagliflozin users (0.55 [0.26–1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27–0.95]; dapagliflozin: 0.66 [0.25–1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87–2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01–3.54] mL/min/1.73 m2 per year). CONCLUSIONS This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline.

SGLT2i, empagliflozin and canagliflozin, have been shown to reduce the incidence of major adverse CV events (MACE), all-cause mortality (ACM) and renal events in CV outcomes trials (CVOTs), with robust real-world evidence (RWE) suggesting class effect benefits. In the exenatide CVOT EXSCEL, ∼10% of patients took an SGLT2i with ∼5% use of dapagliflozin (DAPA). Effects of all SGLT2i, and DAPA alone, on MACE, ACM, and eGFR were analyzed in EXSCEL participants randomized to placebo. Propensity-matched cohorts (including by study visit) of SGLT2i users and non-users (n=709 per group) were generated, based on their last measured characteristics before SGLT2i initiation. Subsequent time-to-first adjudicated MACE and ACM were compared using a Cox regression. Decline in eGFR over time (slope) was quantified in the matched cohorts using a mixed model repeated measurement (MMRM) analysis. SGLT2i overall, and DAPA alone, numerically decreased the MACE hazard ratio, and SGLT2i significantly reduced the ACM risk (Table). The eGFR slope was improved significantly for SGLT2i overall and DAPA alone (Table). This post-hoc EXSCEL analysis supports a beneficial class effect for SGLT2i on MACE, ACM, and renal function, consistent with published CVOTs, Real-World data, and for DAPA alone. DECLARE, the ongoing DAPA CVOT, will complete in 2018.Time-to-First Adjudicated EventPropensity-matched cohortnEventsSubject-years of follow-upCrude rate (events/100 subject-years)Unadjusted hazard ratio (95% CI)Adjusted hazard ratio (95% CI)MACEaNo SGLT2i709449904.45SGLT2i709288223.410.78 (0.48–1.27)0.79 (0.49–1.28)No DAPA354224844.54DAPA354114082.690.59 (0.28–1.24)0.55 (0.26–1.15)All-cause mortalityNo SGLT2i7093711083.34SGLT2i709148711.610.48 (0.26–0.89)0.50 (0.27–0.95)No DAPA354135382.42DAPA35474321.620.66 (0.25–1.69)0.66 (0.25–1.72)MMRM analysisPropensity matched cohorteGFR slope (standard error)Treatment effect (95% CI)p-valueeGFR slope (mL/min/1.73m2/year) No SGLT2i−0.91 (0.26)SGLT2i+0.87 (0.37)+1.78 (0.87–2.69)0.00013No DAPA−1.04 (0.37)DAPA+1.24 (0.54)+2.28 (1.01–3.54)0.0004aMACE: a composite endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke Disclosure L. Clegg: Employee; Self; AstraZeneca. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Consultant; Self; Janssen Research & Development, Fresenius SE & Co. KGaA. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. W. Tang: Employee; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. S. Bachina: Employee; Self; AstraZeneca. R.D. Fox: None. P. Fenici: Employee; Self; AstraZeneca. M. Thuresson: Consultant; Self; AstraZeneca. R.J. Mentz: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc. A.F. Hernandez: Research Support; Self; AstraZeneca, GlaxoSmithKline plc., Merck & Co., Inc.. Consultant; Self; Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. R.R. Holman: Research Support; Self; AstraZeneca, Merck & Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck & Co., Inc.. Other Relationship; Self; AstraZeneca.